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Amorphous forms of risedronate monosodium

a technology of risedronate and monosodium salt, which is applied in the field of amorphous forms of the monosodium salt of 3pyridyl1hydroxyethylidene1, 1bisphosphonic acid, can solve problems such as significant instability, and achieve the effect of improving total bioavailability

Active Publication Date: 2007-06-21
ZENTIVA AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0021] Drying can be carried out at temperatures in the range of 50° C. to 200° C. Higher temperatures during drying are not detrimental and do not cause decomposition of the substance being dried, since the solution is exposed thereto for only a short period of time. In preparation of the amorphous form by drying the crystalline pentahydrate at higher temperatures partial decomposition occurs.
[0024] For the amorphous risedronate having the higher water content it has been surprisingly found out that it can be prepared in the solid state and that it does not transform to the crystalline form upon storing. These amorphous risedronates having the higher water content have the advantage of not being hygroscopic, thus avoiding necessity of being stored without access of air humidity.
[0028] A composition that can be directly compressed is an extraordinarily advantageous combination, where a mixture of mannitol and microcrystalline cellulose plays the role of the diluent. This combination displays exceptional stability, especially in the wet environment.
[0034] Bisphosphonates are always administered to patients when fasting, i.e. before foods; the preparation Actonel (sodium risedronate active substance) is to be administered at least 30 mins before the first daily meal. In these circumstances, residence of the medicament in the stomach lasts only several minutes. It follows from the results of Example 10 below that while risedronate according to this invention would remain in the solution in the stomach and would pass to the small intestine, wherein it would be absorbed into blood, risedronate administered in the usual form of pentahemihydrate would partly or wholly precipitate from the stomach juices and would leave the stomach in the form of a precipitate. A tablet containing the risedronate according to this invention, hence, has conditions for the active substance to pass into blood in a greater amount, which would improve total bioavailability.

Problems solved by technology

This can be a significant source of instability of this form.

Method used

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  • Amorphous forms of risedronate monosodium
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Examples

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example 1

[0048] A Method of Preparation of the Amorphous Form of Risedronate Sodium:

[0049] 10 g of crystalline form of risedronate pentahydrate (according to WO 2004 / 037252) was dried at 130° C. for 5 hours. 8.46 g of the amorphous form of risedronate sodium was obtained, which was characterized with X-ray powder diffraction (FIG. 4), 13C and 31P Cp MAS NMR spectra (FIGS. 2 and 3) and Raman spectra (FIG. 1) and TGA (thermogravimetric analysis) (FIG. 5), according to which the prepared amorphous risedronate contained 4.7% of water.

example 2

[0050] A Procedure of Preparation of the Semi-Crystalline Form of Risedronate Sodium:

[0051] 10 g of crystalline form of risedronate pentahydrate (according to WO 2004 / 037252) was dried at 110° C. for 20 hours. 8.2 g of the semi-crystalline form of risedronate sodium was obtained, which was characterized with X-ray powder diffraction (FIG. 9), 13C and 31P Cp MAS NMR spectra (FIGS. 7 and 8) and IR spectra (FIG. 6). Thus prepared semi-crystalline risedronate contained 1.7% of water. After one month storage on the open air at laboratory temperature the content of water increased to 3%.

example 3

[0052] A Procedure of Preparation of the Semi-Crystalline Form of Risedronate Sodium:

[0053] 10 g of crystalline form of risedronate pentahydrate (according to WO 2004 / 037252) was dried at 50° C. for 5 hours, then the temperature was elevated to 100° C. and drying was continued for 10 hours. 8.5 g of the semi-crystalline form of risedronate sodium was obtained, which was characterized with X-ray powder diffraction, 13C and 31P CP MAS NMR spectra and IR spectra. Thus prepared semi-crystalline risedronate contained 1.5% of water.

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Abstract

The monosodium salt of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid in new amorphous forms, methods of preparation and a pharmaceutical formulation.

Description

TECHNICAL FIELD [0001] The invention concerns new amorphous forms of the monosodium salt of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid (formula I) and methods for preparing the same. BACKGROUND ART [0002] Geminal bisphosphonates, such as for example salts of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid (RISEDRONATE) or 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (ALENDRONATE) have been used for already some time to treat bone diseases and for management of the metabolism of calcium. [0003] Preparation of risedronic acid consists in the reaction of 3-pyridylacetic acid with phosphorous acid and phosphorus trichloride and subsequent hydrolysis of the resulting intermediates. A general method of this preparation of bisphosphonic acids was presented in JP 80-98193 (1980), JP 80-98105 (1980) of Nissan Chemical Industries and in the article of W. Ploger et al., Z. Anorg. Allg. Chem., 389, 119 (1972). Preparation of risedronate was presented in EP 186405 (1986) o...

Claims

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Application Information

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IPC IPC(8): A61K31/675C07F9/58
CPCC07F9/582C07F9/58A61P19/00
Inventor RICHTER, JINDRICHJIRMAN, JOSEFPETRICHOVA, HANA
Owner ZENTIVA AS